We have discovered in the bone of several animal species the presence of an unique protein, the Gla protein. We have developed specific radioimmunoassays for several species of Gla protein and have demonstrated that it is present in readily detectable quantities in both serum (or plasma) and urine. In preliminary studies in humans with one of the radioimmunoassay procedures, we have determined that the measurement of Gla protein can be an index of bone turnover. For example, its serum concentration is increased in patients with Paget's disease of bone and in hyperparathyroidism and decreases with therapy. To pursue these observations, we plan a systematic study of the Gla protein in normal and abnormal skeletal metabolism in humans and experimental animals and in vitro. In humans we shall study the Gla protein in normal subjects of both sexes and in patients with a variety of skeletal disorders. The measurement of Gla protein will be related to the clinical course of the disease, including treatment regimens, and other parameters of calcium and skeletal metabolism such as plasma calcium, phosphorus, alkaline phosphatase, PTH, calcitonin, and vitamin D metabolites and bone radiography, densitometry, and biopsy. In animal studies we shall evaluate the effect on Gla protein of perturbations to skeletal homeostasis such as dietary manipulations; surgery on the thyroid and parathyroid glands, the gonads, the kidneys and ureters; and the exogenous administration of substances such as PTH, calcitonin, vitamin D metabolites, diphosphonates, glucocorticoids, anticoagulants, and sex hormones. In vitro studies of bone will also be conducted to determine the effect of experimental manipulations on the dynamics of the Gla protein. These studies should help to define the clinical and biological significance of the Gla protein of bone and may provide a useful and unique biochemical marker for the assessment of bone turnover and skeletal status.